In 1983, the etiological cause of AIDS was determined to be the human immunodeficiency virus (HIV). In 1985, it was reported that the synthetic nucleoside 3′-azido-3′-deoxythymidine (AZT) inhibits the replication of human immunodeficiency virus. Since then, a number of other synthetic nucleosides, including 2′,3′-dideoxyinosine (DDI), 2′,3′-dideoxycytidine (DDC), 2′,3′-dideoxy-2′,3′-didehydrothymidine (D4T), cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (FTC), (−)-cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane (3TC), have been proven to be effective against HIV. After cellular phosphorylation to the 5′-triphosphate by cellular kinases, these synthetic nucleosides are incorporated into a growing strand of viral DNA, causing chain termination due to the absence of the 3′-hydroxyl group. They can also inhibit the viral enzyme reverse transcriptase.
It has been recognized that drug-resistant variants of HIV can emerge after prolonged treatment with an antiviral agent. Drug resistance most typically occurs by mutation of a gene that encodes for an enzyme used in viral replication, and most typically in the case of HIV, reverse transcriptase, protease, or DNA polymerase. Recently, it has been demonstrated that the efficacy of a drug against HIV infection can be prolonged, augmented, or restored by administering the compound in combination or alternation with a second, and perhaps third, antiviral compound that induces a different mutation from that caused by the principle drug. Alternatively, the pharmacokinetics, biodistribution, or other parameter of the drug can be altered by such combination or alternation therapy. In general, combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous pressures on the virus. One cannot predict, however, what mutations will be induced in the HIV-1 genome by a given drug, whether the mutation is permanent or transient, or how an infected cell with a mutated HIV-1 sequence will respond to therapy with other agents in combination or alternation. This is exacerbated by the fact that there is a paucity of data on the kinetics of drug resistance in long-term cell cultures treated with modern antiretroviral agents.
HIV-1 variants resistant to 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (DDI) or 2′,3′-dideoxycytidine (DDC) have been isolated from patients receiving long term monotherapy with these drugs (Larder B A, Darby G, Richman D D. Science 1989;243:1731-4; St Clair M H, Martin J L, Tudor W G, et a. Science 1991;253:1557-9; St Clair M H, Martin J L, Tudor W G, et al. Science 1991;253:1557-9; and Fitzgibbon J E, Howell R M, Haberzettl C A, Sperber S J, Gocke D J, Dubin D T. Antimicrob Agents Chemother 1992;36:153-7). Mounting clinical evidence indicates that AZT resistance is a predictor of poor clinical outcome in both children and adults (Mayers D L. Lecture at the Thirty-second Interscience Conference on Antimicrobial Agents and Chemotherapy. (Anaheim, Calif. 1992); Tudor-Williams G, St Clair M H, McKinney R E, et al. Lancet 1992;339:15-9; Ogino M T, Dankner W M, Spector S A. J Pediatr 1993;123:1-8; Crumpacker C S, D'Aquila R T, Johnson V A, et al. Third Workshop on Viral Resistance. (Gaithersburg, Md. 1993); and Mayers D, and the RV43 Study Group. Third Workshop on Viral Resistance. (Gaithersburg, Md. 1993)). The rapid development of HIV-1 resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) has also been reported both in cell culture and in human clinical trials (Nunberg J H, Schleif W A, Boots E J, et al. J Virol 1991;65(9):4887-92; Richman D, Shih C K, Lowy I, et al. Proc Natl Acad Sci (USA) 1991;88:11241-5; Mellors J W, Dutschman G E, Im G J, Tramontano E, Winkler S R, Cheng Y C. Mol Pharm 1992;41:446-51; Richman D D and the ACTG 164/168 Study Team. Second International HIV-1 Drug Resistance Workshop. (Noordwijk, the Netherlands. 1993); and Saag M S, Emini E A, Laskin O L, et al. N Engl J Med 1993;329:1065-1072). In the case of the NNRTI L'697,661, drug-resistant HIV-1 emerged within 2-6 weeks of initiating therapy in association with the return of viremia to pretreatment levels (Saag M S, Emini E A, Laskin O L, et al. N Engl J Med 1993;329:1065-1072). Breakthrough viremia associated with the appearance of drug-resistant strains has also been noted with other classes of HIV-1 inhibitors, including protease inhibitors (Jacobsen H, Craig C J, Duncan I B, Haenggi M, Yasargil K, Mous J. Third Workshop on Viral Resistance. (Gaithersburg, Md. 1993)). This experience has led to the realization that the potential for HIV-1 drug resistance must be assessed early on in the preclinical evaluation of all new therapies for HIV-1.
2′,3′-Dideoxy-2′,3′-didehydro-5-fluorocytidine (D4FC) is a known compound. European Patent Application Publication No. 0 409 227 A2 filed by Ajinomoto Co., Inc., discloses β-D-D4FC (Example 2) and its use to treat hepatitis B. Netherlands Patent No. 8901258 filed by Stichting Rega V. Z. W. discloses generally 5-halogeno-2′,3′-dideoxy-2′,3′-didehydrocytidine derivatives for use in treating HIV and hepatitis B (“HBV”). U.S. Pat. No. 5,703,058 discloses a method for the treatment of HIV and HBV infection that includes administering an effective amount of β-L-D4FC in combination or alternation with cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane, 9-[4-(hydroxymethyl)-2-cyclopenten-1-yl)-guanine(carbovir), 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir), interferon, 3′-deoxy-3′-azido-thymidine (AZT), 2′,3′-dideoxyinosine (DDI), 2′,3′-dideoxycytidine (DDC), (−)-2′-fluoro-5-methyl-β-L-ara-uridine (L-FMAU) or 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T). U.S. Pat. No. 5,905,070 discloses a method for the treatment of HIV and HBV infection that includes administering an effective amount of β-D-D4FC in combination or alternation with cis-2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane, cis-2-hydroxymethyl-5-(cytosin-1-yl)-1,3-oxathiolane, 9-[4-(hydroxymethyl)-2-cyclopenten-1-yl)-guanine (carbovir), 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir), interferon, 3′-deoxy-3′-azido-thymidine (AZT), 2′,3′-dideoxyinosine (DDI), 2′,3′-dideoxycytidine (DDC), (−)-2′-fluoro-5-methyl-β-L-ara-uridine (L-FMAU) or 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T).
It is an object of the present invention to determine the optimal administration of β-D-D4FC for the treatment of HIV.
It is another object of the present invention to provide a method and composition that includes β-D-D4FC for the treatment of patients infected with HIV that exhibits advantageous or improved pharmacokinetic, biodistribution, metabolic, resistance or other parameters over administration of β-D-D4FC alone.
It is yet another object of the present invention to provide a method and composition for the treatment of patients infected with HIV in which β-D-D4FC is administered in combination or alternation with a second compound that acts synergistically with β-D-D4FC against the virus.
It is still another object of the present invention to provide a method and composition for the treatrnent of patients infected with a drug resistant form of HIV.
It is another object of the present invention to provide a method and kit to assess how to best administer β-D-D4FC.